Lecture 13 - Mucosal Immunity - ON FINAL

Question 1

What does the mucosal immunity include? (7)

Answer 1

1. Gastrointestinal Tract - gut associated lymphoid tissue (GALT)
2. Respiratory Tract - bronchial associated lymphoid tissue (BALT)
3. Nasal associated lymphoid tissue - NALT
4. Genitourinary Tract
5. Lacrimal Glands
6. Salivary Glands
7. Mammary Glands

Question 2

Define the induction process of the response

1. What cells take up antigens entering the digestive tract?
2. Where do these cells transfer the antigen
3. How are these cells formed?
4. What is another way antigen can be taken up?
5. Where are these antigens presented?

Answer 2

1. antigens entering the digestive tract are taken up by specialized mucosal cells called M cells
2. M cells internalize the antigen and transport it across the epithelium where antigen can be taken up by APCs such as Dendritic Cells
3. M cells are formed in mucosal epithelium in response to signals from lymphocytes
4. Antigen can be taken up by DC that have dendrites extending through the epithelial tight junction into the lumen.
5. Antigens are then presented to lymphocytes (in the intestine these are in Peyer’s patches)

Question 3

What are peyer’s patches?

Answer 3

Location in intestine where antigens are presented to lymphocytes by DC’s

Question 4

1. What happens once lymphocytes leave the mucosal site?
2. Via the ________ the lymphocytes exit the lymph and enter circulation.
3. What addressins “home” the lymphocytes to positions in the mucosal lamina propria?
4. What happens at the effector sites to the B cells?

Answer 4

1. Travel to the mesenteric lymph nodes
2. Thoracic Duct
3. alpha4beta7
4. B lymphocytes in the peripheral tissues PROLIFERATE AND DIFFERENTIATE into IgA secreting plasma cells at effector sites

Question 5

B cells in the mucosa are selectively induced to produce _______ rather than any other isotope.

What mediates this switch of B cells?

What cells are also very important for the mucosal immune response?

Answer 5

1. DIMERIG IgA
2. Mediated by specific cytokines produced by T cells in the inductive sites
3. Conventional T cells (CTLs)

Question 6

Induction of a response in a mucosal site also induces what other response?

Does this work vice versa?

What does this indicate about the subsets of T and B cells?

Answer 6

1. SYSTEMIC RESPONSE
2. Does not work in reverse: systemic response cannot cause mucosal response (ex: tetanus vaccine)
3. Indicates that a mucosal encounter with antigen generates subsets of T and B cells that home to mucosal sites and also to spleen & regional nodes.

Question 7

What population of lymphocytes are found in the gut epithelium?

Answer 7

Mostly CD8+ T cells

• function is not apparent, but may readily kill infected epithelial cells

Question 8

Mucosal Response to Infection:

Innate immune mechanisms in the mucosa eliminate most intestinal infections rapidly via what receptors?

What happens once the TLR’s and Nod Like receptors recognize the bacteria?

Answer 8

Pattern Recognition Receptors –> TLR’s!

2. activate NF-Kb
   - main function is to express a number of inflammatory cytokines/chemokines in order to activate neutrophils, macrophages, and dendritic cells

Question 9

What is the function of NF-Kb?

Answer 9

• main function is to express a number of inflammatory cytokines/chemokines in order to activate neutrophils, macrophages, and dendritic cells

Question 10

What happens in IgA Deficiency states?

What is normal in these patients?

Answer 10

Most common primary immune deficiency

• Normal cell mediated immunity and serum antibody responses

Question 11

What are 4 reasons to suspect selective IgA deficiency?

Answer 11

1. Family history of IgA deficiency of agammaglobulinemia
2. High incidence of oral infections
3. Frequent respiratory tract infections
4. Chronic Diarrhea

Question 12

What disease are often associated with selective IgA deficiency?

Answer 12

1. autoimmune deficiency –> including SLE
2. Juvenile rheumatoid arthritis
3. Thyroiditis

• IMMUNOGLOBULIN therapy is NOT indicated, as the patients normal antibody response can produce anti-IgA antibody in response to IgA treatment
• people with complete absence of IgA may develop allergies or even anaphylactic shock

Question 13

What is the predominant Ig in mucosal secretions?

Answer 13

IgA

Question 14

How is IgA found in serum? In mucosal secretions?

Answer 14

1. monomeric

2. Dimeric - 96% = secretory IgA or sIgA

Question 15

What two things are required for production of secretory IgA?

Answer 15

1. Plasma cells in the lamina propria

2. Epithelial cells of the mucosa

Question 16

Describe the steps to form sIgA:

1. Dimeric IgA (2 monomeric joined by J chain) is produced by ______ cells in ______.
2. It then binds to the ________ on the basal surface of ______ cells.
3. This complex is endocytose and transported through the cell and to the ________ for release.

What happens during the transport?

What remaining component is bound to dimeric IgA?

Answer 16

1. Plasma cells in the mucosal lamina propria
2. polymeric immunoglobulin receptor (pIGR- only for IgA and IgM) on the basal surface of mucosal epithelial cells
3. Lumenal surface
4. pIGR is cleaved and small fragment is lost
5. Secretory component is covalently bout to dimeric IgA
   - IgA is secreted at the mucosal surface as numeric IgA covalently bound to the dimeric IgA

Question 17

What are the only immunoglobulins capable of binding and being transported by pIGR?

Answer 17

polymeric: IgA and IgM

Question 18

What is the result in mice that are deficient for pIgR? (2)

Answer 18

1. Exhibit the expected decreases in IgA transport

2. Leads to an increased mucosal leakiness

Question 19

What are the 4 main functions of IgA at mucosal surfaces?

Answer 19

1. Barrier function
2. Intraepithelial Viral Neutralization (IEL)
3. Excretory Immunity
4. Passive Immunity

Question 20

Describe the following functions of IgA:

1. Barrier function
2. Intraepithelial Viral Neutralization (IEL)

Answer 20

1. Barrier function

• sIgA can bind to bacteria and viruses and prevent their adherence an invasion into mucosal tissues
• sIgA can neutralize many viruses in this way, including polio, hepesvirus, coxsackie virus and ratifiers
• SIga can neutralize BACTERIAL toxins also at the mucosal surfaces

2. Intraepithelial Viral Neutralization (IEL)
   - IgA that is internalized by mucosal epithelial cells (via pIgR) may contribute to intracellular viral inactivation

Question 21

Describe the following functions of IgA:

3. Excretory Immunity
4. Passive Immunity

Answer 21

3. Excretory Immunity
   - viral particles that complex with dimeric IgA in the lamina propria may be endocytose and transported out by the pIgR pathway
4. Passive Immunity
   - sIgA in breast milk provides passive immunity to infant

Question 22

What are the 2 advantages and the 2 disadvantages of Oral Immunization with Mucosally Administered Antigens?

Answer 22

Advantages:

1. Ease of administration (oral)
2. Generates BOTH mucosal and systemic immunity

Disadvantages:

1. Difficulty in eliciting robust response (need inflammation)
2. Response may not be long-lasting

Question 23

What is the response to most antigens in the mucosa?

Answer 23

TOLERANCE

• the type of antigen (pathogenic antigen or non-dangerous commensal bacteria) is critical to eliciting the appropriate response

Question 24

What is the key feature to distinguish between the induction of an IMMUNE RESPONSE and the induction of TOLERANCE?

Which types of encounters generally induce an immune response?

Answer 24

INFLAMMATION

2. Inflammation!
   - antigen encountered in the absence of inflammation = TOLERANCE (ex: food antigens)

Question 25

State whether the following induce an immune response or tolerance: 1. Food antigens 2. Microbes 3. Peptides

Answer 25

1. Food antigens - TOLERANCE 2. Microbes - cause inflammation = IMMUNE RESPONSE 3. Peptides - induce tolerance, unless attached to mucosal adjuvant such as CHOLERA TOXIN

Question 26

What is responsible for development of the immune system?

Answer 26

INTESTINAL BACTERIA - germ free animals have almost no secondary lymphoid tissues including mucosal tissues

Question 27

Recent studies suggest that mucosal tolerance is mediated by ________. State whether this depends on immature or mature cells of this kind.

Answer 27

Mucosal Dendritic Cells a) immature dendritic cells signal and induce CD4 T cells to differentiate into Treg cells or Th3 cells IN PRESENCE OF COMMENSAL BACTERIA b) in presence of invasive microorganisms - penetrate epithelium to activate dendritic cells in order to activate DC's in mature cells --> co-stimulatory ligands bind --> induce CD4 T cells to differentiate into Th1 and Th2!!!

Question 28

What does treatment with antibiotics eliminate? Why is this so serious?

Answer 28

1. Eliminates a large proportion of the commensal organisms and allows pathogens to proliferate and cause disease 2. Can predispose people to C. Difficile - only affects people taking antibiotics (result = lack of commensal bacteria, so the C. Difficile gains a foothold and produces toxins that cause mucosal injury) - neutrophils & RBCs leak into the gut between injured epithelial cells!

Question 29

What are the homing signals for T cells to enter Peyer's Patches from blood vessels? What are the homing signals for activated T cells that home to the LAMINA propria and Intestinal epithelium of small intestine?

Answer 29

1. CCR7 and L-selection | 2. Alpha4:Beta7 integrin and CCR9

Question 30

Induction of NALT leads to more robust response where as opposed to the GI sites?

Answer 30

Respiratory Sites